# Targeting trained immunity and Th1/Th17 axis with combination adjuvants

> **NIH NIH U01** · UNIVERSITY OF CHICAGO · 2024 · $600,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The lack of effective vaccines against most infectious diseases is largely a result of our fundamental lack of
understanding of mechanisms involved in protective immunity. Adjuvants incorporated into vaccine formulations
have a major impact on vaccine efficacy via modulating and prolonging host immune responses; however, our
understanding of their underlying mechanism(s) of action in driving specific immune parameters is incomplete.
While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that
significantly impact human health remain without an effective vaccine. For example, one-fourth of the world's
population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1,
the leading infectious disease killer in the world. It is likely that for TB, and other major infectious diseases (e.g.
AIDS and malaria), new adjuvants or adjuvant combinations will be essential for instructing a protective immune
response. We and others have shown that targeting both the type 1 T helper (Th1) cells and type 17 T helper
(Th17) cells enhance vaccine-induced immunity for TB5-8. Additionally, we have recently demonstrated that live
vaccines (e.g. BCG) and adjuvants (e.g. β-glucan) generate innate memory response, termed trained immunity,
via epigenetic reprogramming of monocytes/macrophages, thereby conferring protection against Mtb
infection9,10. These data together suggest that combination adjuvants targeting both innate trained immunity
and adaptive Th1/Th17 cellular responses can enhance protective immunity against pathogens. Thus,
defining the mechanisms of action of combination adjuvants that generate potent trained immunity and protective
Th1/Th17 axis, are the overall goals of this proposal. In the current proposal, we hypothesize that combinations
of adjuvants that drive Th1 responses (AS01 or UM-1007, a novel TLR7/8 agonist) and Th17 responses (β-
glucan, nanoemulsion, or UM-1098, a novel Mincle agonist) will result in Th1/Th17 adaptive responses and/or
enhance trained immunity. We will achieve these overall goals through the following four Specific Aims. Specific
Aim 1: To determine the mechanisms by which combination adjuvants elicit Th1/Th17 immune responses.
Specific Aim 2. To determine the impact of combination adjuvants on hematopoietic stem cells and trained
immunity. Specific Aim 3. To determine whether use of combination adjuvants improves recall Th1/Th17
responses and trained immunity upon challenge. Specific Aim 4. Determine the mechanism of action of
combination adjuvants in a pre-clinical human-like rhesus macaque model. Together, the aims of this study will
map out the pathways induced by combination of adjuvants that effectively drive Th1/Th17 responses and trained
immunity. Through Mtb challenge studies, we will demonstrate whether the mechanisms by which Th1/Th17 and
trained immunity are elicited are involved in protection again...

## Key facts

- **NIH application ID:** 10842453
- **Project number:** 5U01AI160406-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Maziar Divangahi
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $600,000
- **Award type:** 5
- **Project period:** 2021-07-26 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842453

## Citation

> US National Institutes of Health, RePORTER application 10842453, Targeting trained immunity and Th1/Th17 axis with combination adjuvants (5U01AI160406-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10842453. Licensed CC0.

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